As humans age, we experience inevitable physiological changes in many areas, including motor activity. In fact, age-dependent progressive decline in motor activity represents one of the most prominent physiological changes in aging animals and humans. Neuromuscular junctions (NMJs) are the functional units that connect motor neurons and muscles. Deficits at NMJs are believed to underlie age-dependent decline in motor function. Despite extensive studies, the mechanisms by which NMJs undergo functional decline during normal aging are not well understood. It also remains a challenge as to whether and how intervening functional decline at NMJs can improve motor function in the elderly and ultimately extend lifespan. The nematode C. elegans has recently emerged as a good model system for aging studies because of its short lifespan and amenability to genetic manipulation. During aging, C. elegans also exhibits many aging phenotypes that resemble those found in higher organisms, including the age-related decline in motor activity. However, the same question arises as to what mechanisms may underlie the progressive decline in motor activity observed in aging worms. Recently, we have performed the first functional analysis of the aging motor neurons and muscles throughout the lifespan of C. elegans. Our results suggested that the progressive decline in the synaptic vesicle fusion followed by that in quantal size and vesicle docking/priming of motor neurons significantly contribute to the age-related functional decline of NMJs. Therefore, in this proposal, we aim to further address the following unanswered questions (Aim 1): What are the mechanisms underlying the observed functional decline in synaptic vesicle fusion in motor neurons in early life? Do muscles contribute to the observed functional decline in motor neurons? A long-term goal of our research is to ultimately develop new therapeutic strategies that could prevent or delay the age-related declines in mobility and increases in fatigability that often occur in the elderly population. Thus, in the second part of this proposal, we will focus on investigating whether applying genetic (Aim 2) and pharmacological (Aim 3) interventions specifically targeting the motor neuron synaptic transmission to aged worms can ameliorate NMJ functional decline and ultimately extend lifespan.